Recent diagnostic and therapeutic advances in oncology have led to greater survival rates in children and young adults with malignancies. However, in women, while cancer therapies improve long-term survival, such treatments often lead to premature ovarian failure and infertility related to early ovarian aging. As more young women survive cancer and lead productive lives, these concerns are becoming increasingly important. Nevertheless, it is difficult to predict if and when such problems will arise and what the severity and duration will be. Indeed, there are no early clinical signs of decreased ovarian dysfunction and even young women who maintain cyclic menses after therapy are at high risk of infertility, early menopause, and long-term health problems related to early ovarian failure. While it has recently been observed that hormone and ultrasound measures of ovarian reserve are impaired in long term survivors of cancer, it is not clear whether these measures reflect fertility potential and time to menopause in this population. We have intriguing preliminary data to suggest that childhood and young adult cancer survivors exposed to high risk cancer therapies in their mid 20's have hormone and ultrasound measures of ovarian reserve similar to naturally aging women in their mid 40's. The current proposal represents the first comprehensive and appropriately powered investigation of the acute and long-term reproductive consequences of cancer treatment in adolescent and young women. The proposed aims are 1) to assess acute changes in reproductive function during and after chemotherapy in cancer patients, 2) to assess the long-term reproductive function of women exposed to cancer therapies and make comparisons to similarly aged and late reproductive aged unexposed females and 3) assess for the presence of follicular and luteal dysfunction in cancer survivors by comparing daily urinary hormone metabolites over 2 menstrual cycles between subjects exposed to high dose alkylating agent therapy and 2 unexposed populations of females. The findings of this proposal will help confirm our preliminary findings, and will be critical in estimating the reproductive window in cancer survivors. In addition, this research will expand our knowledge of the effects of cancer therapy and will help to establish a method to predict the impact of chemotherapy prior to treatment. Ultimately, this data will be critical to determine if these measures are useful in predicting the timing and extent of ovarian dysfunction as well as fertility potential in this population and will have a major impact on the quality of life of girls and women who survive cancer. PUBLIC HEALTH RELEVANCE: Recent diagnostic and therapeutic advances in oncology have led to greater survival rates in children and young adults with malignancies. However, while cancer therapies, especially alkylating agents, improve long- term survival, such treatments often lead to premature ovarian failure and reproductive dysfunction related to early ovarian aging. This proposal will assess the immediate and long-term changes in reproductive function in young females exposed to chemotherapy. The findings of this research will have a major impact on patient counseling and targeting fertility preservation efforts.